Imidazole derivatives. Histidine decarboxylase inhibitors - Journal of

Inhibition of histidine decarboxylase by imidazole derivatives. James L. Kelley , Ed W. McLean , Carl A. Miller. Journal of Pharmaceutical Sciences 19...
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t h ~ tcstosterone i (Tablr 1). On t h e other h n d , tht, Ay(141compounds were only wr~alilyactive; in no case w i i h potency higher than 0.2 of the corresponding teutohterone activity obherved. 'l'hs could mean that thc hypothehis of enhancement due to flattening toward the /3 face. i. incorrect. hlternntivel!~, the presence of thca double bond, 01- thri :ibhence of t h e S$- or 14a-H m:iy bta I (+poii\iblc for th(1 Ion. o i ~ k ~ of'r ;ictivit\ Experimental Sectionb

5a-Androsta-8(14)-3,17-dione(2). ~h ~iiliitioti o f 2 g I)!' 1' 200 1111 of lIeyCO aau oxidized with Jones reagetit at t ' o o t i i temp. i-PrOII was added to destroy the excess Jones reagetit, ice water was added, arid the l I e 2 C 0was removed ruider rediicetl pressiire. The ppid powder n-as filtered t o afford 1.S g of prodi i c t , nip 144-148', which was re .td from ;\leOH-HsO t o give a >ample: mp 145-149'; itmi w (19 rja), 1.10 (1% IT:^^. [ a ] 2 0+:i47' ~) (c, 1, CHCIa). h a l . (CleHsGO1) C, H. 3,3-Dimethoxy-5~androst-S(14)-en-17-one (3).--A w l i i t i i ) i i of 1 . 3 g of 2 and 1.3 g of Se02 i t 1 60 nil of 1LeOI-I was heated :it .iOo for 15 miii. It was cooled t o roi~intemp :tiid a soliiiioti ( i f 2..i ,q of KO11 in 20 ml of 11eOH was adtied to make the soliitioti :~lkdirie. I t was poiired itito ice water, :tiid the pptd powclet. w : t h filtered to afford 1.3 g of (.ride prodiict, mp 103-104". It was recrystd from LteOH cotitaitiitig 1 drop of methatiolic KUII t o give 3: nip 106-lox"; nmr 0.70 (19 H a ) , 1.07 (IS Hi), [a]'Oi) $222" (CJ 1e. ?'tic, iti

w : ~ - c.oiiled itrid the ppttl powder was filtered 10 d i ' o t ~ l 5 , lllp lhObls;io. It W8.S N" 1 f r o m AIeOII-I120 t o givr inateri:il, i r i p 1%-1S;J", [o~]'"II 7 c, ll,';?CHCl,). . I n n / . ( C i ' d I J i a O i I C:, 11. 17fi-Hydroxy-5a-androst-S(14j-en-3-one Acetate ( 6).---A d i t t i o t i of 0 . 1 g of 5 i t , 1 ml of C&X was added to 0.1 ml of A c s l ) :itid the niixtrire was kepi. at ~ ( J O I I Itemp for 24 hr. Ice water .-oliitiori 0.7 g Of

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ivere determined wich a Thomaa-Hoover apparatuk witli a corrected thermometer. 1Iicroanalyses were performed ti). t I I P Ilir.roanaIytica1 Ilepartment, University of California, Berkeley, ('alif. N i n r spectra mere obtained a t a field strength of 60 RIIIz on samples i n ( ; l ) C l s sollition on a T'arian .\ 60.\ i n s t r i i m e n t tising TSIS a s internal staiiI rotaticin, u e r ~o l i i a i n w l i n :< 0,5- ~ H ~ i l I l ? \\'Irerv L ? ~ . a i i a I , r ~ wn r r indicair> b y i u t t o l . o f I lie v l c ~ i i i r ~ i toi r frinciiuni. anal>.tiral r P * i i l t s rltttaineil for those e l e i n p l i t o r f i i l r c ~ IU t I, \vc>rp n i i l i i i i _ t O . i ' , ; of t l i v I tieut etical \.alriea. ( t i ) AIrlting point8

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Hist:iniiii(~ h:is b c w iinplicattd i i i :i iiiinibtAr of physiologicwl procc :1mong them) the regulatioll . 4 gastric secretion.^ growth :ind of the microcircuh repair processes,R :ind certain hormone :~ctions.' Somf) clinical conditions in which histamine plays a i d ( : :ir ind allergy, wound healing, inflamation, : ~ n d . 'rht. discovery of :in inducible. specific irbosyhsc (HD) in manimdi:tri tissues ; ~ 1 thc tlrvrlopnwnt of srnsit,ivi::t iy.4 h:is o p t ' i ~ du p I I ~ W :ippro:iches t80 tlw uuderstandirig of t,he ph\.siologic:tl a r i d pathological iule of hist:miint.. In recent, ye:~rs. interest in histidiiie decarboxylase inhibitors :IS tools ii: such studies aiid :is agents for the treat,nieritof disord(~r5 ,?m3

11) T o rvlium inquuir. .Ihurthi l i e d i r e c t e i l . ( 2 ) TV. ii'. Douglas i n t h e "Plmrnracologicai I3auia nf Therapeutics." La. 5. Goodman a n d A . Gilman. Ed., Macrnillan Co.. N e w York. S . Y ~ 1965, , PI, 6 16-627. 13) D. XI. Shapiieril arid I ) . ,\lackah, I ' r u y r . \ I d f ' l ( p r n , , 6 , lP!l i l i l ( i i i . ( 4 ) R . I!-. Schayer. I ' T o ~ Allergy, ~. 7 , 187 (lQ6:3), 1 5 ) J. E. Fischer a n d S. H . Snyder, F e d . f'roc.. F e d . A m ~ r S. o r . l c p . Bid., , w t . Hid. . \ I d , 6, t i ! (

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Journal of .lfcdicinal Chemistry, 19'70, Val. 1.3, -Yo. 5 969

Histidine

decarboxylase inliillit ion

c

1

nl H

2

II

3

No

/C

AIp OC'J

3 ield

(%IC

187-188

-_ I 3

20

CioH9ClSsO. HCl

200-201

60

47

H

CioHgClNsO .HCI

152-154

31

34

4

I1

CioHsClSsO .HCI

188-180

60

28

5

11

193-195

56

50

6

I1

192-193

66

43

7

H

177-179

-13

2x

8

H

176-177

51

45

9

H

187-189

56

27

10

H

185-196

48

27

11

H

222-223

43

0

12

II

124-125

!)O

ti5

1;:

11

176-177

93

39

14

H

200-201

h"

i!)

15

H

123-124

S5

--

16

H

184-186

46

--

17

H

164-165

52

- a-

1s

H

142-1 43

4-5

29

199-200

5:i

0

180-182

48

15

222-225

46

0

I

I9

H

20

H

21

CioHsClnKsS .HC1

U+&KH>

11

All compounds listed ill the table were analyzed for C, H, N aiid the results were within &0.4c;, of theoretical. were det'ermiiied in a Thomas-Hoover capillary apparatus and are uncorrected. All compounds tested at -11. 'I

I I

I 1

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